Optically active tert-alkyl 7-(2-oxo-5-carbonyloxypyrrolidinyl) heptanoates

ABSTRACT

Optically active tert-alkyl 7-2(oxo-5-carbonyloxypyrrolidinyl)heptanoates and their preparation by reaction of racemic tert-alkyl 7-(2-oxo-5-carboxypyrrolidinyl)heptanoate with an optically active amine to form resolved d or l amine salts which are then reacted with acid to form resolved acid intermediates. Esterification of these acid intermediates produces resolved d or l esters which are useful to make optically active 8-azaprostanoids having biological activity.

BACKGROUND OF THE INVENTION

This invention concerns optically active (resolved) tert-alkylpyrrolidinyl heptanoate intermediates which are useful for makingbiologically active 8-azaprostanoids.

There is relatively little art concerned with optically active8-azaprostanoids. U.S. Pat. No. 4,113,873 (Himizu) discloses the laevo15α-isomer of ##STR1## where R' is ethyl or n-propyl, or apharmaceutically acceptable salt thereof. Also described is a processfor preparing said isomer starting with the aldehyde: ##STR2## where R⁴is lower alkyl. The optically-active (d and l) isomers of this aldehydeare prepared by several reactions starting from d- orl-5-hydroxymethyl-2-pyrrolidone.

U.S. Pat. No. 4,177,346 (Nelson) discloses ##STR3## where A is a singleor cis double bond. W is a tetrazol, R₃ is H, or alkyl of 1 to 5carbons, and R₂ is phenyl. This patent discloses optically active8-azaprostanoids: ##STR4## and their preparation from d orl-pyroglutamic acid. The synthetic sequence is similar to that used inthe Himizu patent in that it also goes through the optically-active5-hydroxymethyl-2-pyrrolidone.

U.S. Pat. No. 3,975,399 (De Franco and Scribner) describes various8-azaprostanoids but does not discuss either stereoisomers or opticalactivity of any of the prostanoids or their intermediates. The racemic8-azaprostanoids of the patent do not have the optical activity of the8-azaprostanoids described herein, nor do they possess the biologicalproperties which are a concomitant of said optical activity.

General methods for resolving racemates are discussed in the literature,for example, in "Advanced Organic Chemistry", Fieser and Fieser,Reinhold Publishing Company, 1961, pages 85 to 89; and "OrganicChemistry", Cram and Hammond, 2nd edition, 1964, McGraw-Hill, pages 174to 176.

SUMMARY OF THE INVENTION

This invention relates to optically active tert-alkyl7(2-oxo-5-carbonyloxypyrrolidinyl)heptanoates of the formula: ##STR5##wherein the asterisk means that one enantiomer is predominant; A is CH₂CH₂, CH═CH (cis or trans); or C.tbd.C; tAlk is a tert-alkyl of 4 to 7carbons; and R is H, alkyl of 1 to 4 carbons, or a protonatedoptically-active amine. The preferred compounds of this invention arethose where Alk is butyl (Bu) or amyl (Am), A is CH₂ CH₂, and R is H,CH₃ or a protonated optically-active amine, especially where the amineis d or l α-methylbenzylamine or d or l ephedrine. Enantiomers areoptical isomers related as object and nonsuperimposable image.

This invention also concerns a process for preparing the opticallyactive tert-alkyl heptanoates described above. The process comprises thesteps, in sequence, of (i) reacting racemic carboxylic acids of theformula ##STR6## with optically active (d or l) amines, thereby formingamine salts of the formula ##STR7## (ii) separating amine salts II fromthe diastereoisomeric amine salt byproducts; (iii) reacting amine saltsII with mineral acids, thereby forming corresponding d or l carboxylicacids of the formula ##STR8## (iv) reacting the d or l carboxylic acidswith an esterification agent, thereby forming compound IV of theinvention wherein R is alkyl of 1 to 4 carbons.

DETAILS OF THE INVENTION

The reaction sequence described above employs racemic carboxylic acids,I, as the starting reagent. It will be appreciated by one skilled in theart that one method for making acids, I, (and the preferred methodherein) is by hydrolyzing the corresponding racemic tert-alkyl7-(2-oxo-5-alkoxycarbonylpyrrolidinyl)heptanoate diesters: ##STR9##

Esters of IV of this invention can be employed to make optically active8-azaprostanoids by reducing IV to the optically active d or ltert-alkyl 7-(2-oxo-5-formylpyrrolidinyl)heptanoate: ##STR10## andreacting said reduction product with dialkyl phosphonates of theformula: ##STR11## where Alkyl is 1 to 4 carbons, to give opticallyactive 8-azaprostanoid ketones of the formula ##STR12## which in turncan be reduced, e.g., by a borohydride reducing agent, to opticallyactive 8-azaprostanoids of the formula: ##STR13## and tAlk converted toR³ by hydrolysis, esterification, salt formation, and the like, wherein

R³ is H, aliphatic-, branched-, or cycloalkyl of 1 to 12 carbons,physiologically acceptable metal cation, or physiologically acceptableamine salt cation;

A is as described above;

R⁴ is H, CH₃ or CF₃ ;

Q is CH₃ or CF₃ ; and

n is an integer from 3 to 7.

Asterisks are employed in formulas set out herein to designate chiralcarbon atoms that exist, by virtue of a resolution step, in one orpredominantly one of two possible absolute configurations. That is: oneisomer is present in enantiomeric excess comprising from slightly morethan 50% up to 100% of the total amount of compound. Compounds havingthese chiral carbon atoms in one, or predominantly one, configurationare referred to as being "optically active" because at least at certainwavelengths these compounds rotate the plane of polarized light.

Generally, the sign and magnitude of the optical rotation will depend onthe particular compound and the wavelength of light used for measurementof optical rotation; to a lesser degree it will also depend on solvent,concentration, and temperature. Wavey lines, representing bonds betweencarbon and OH, mean that a mixture of the two possible absoluteconfigurations is present. Wedge-shaped bonds represent bonds protrudingout of the plane of the paper. Bonds represented by broken linesrepresent bonds extending behind the plane of the paper.

The process of this invention is characterized by employing tert-alkylester reaction intermediates. The initial reactant is the racemicdiester ##STR14## This diester is hydrolyzed by sequential treatmentwith aqueous base and then dilute mineral acid to give tert-alkylester/carboxylic acid, I, in high yield because of the combined effectsof the high reactivity of the 5-carboalkoxy groups of the diester andthe resistance toward saponification of the tert-alkyl esterfunctionality.

The advantage of the tert-alkyl ester functionality as a protectinggroup for the C-1 carboxyl group later is evident because opticallyactive ester, IV, is reduced selectively to the optically activetert-alkyl 7-(2-oxo-5-formylpyrrolidinyl)heptanoate without changing theC-1 functionality.

In the following Columns A and B, the racemic esters of Column A,prepared as described in U.S. Pat. No. 3,975,399, can be hydrolyzed tothe racemic tert-alkyl ester acids I of Column B. Compounds identifiedby the same lower case letter, e.g., a, b, c . . . , belong to the sameseries of reactions. For example, racemic diester (a) of Column Aaffords racemic ester acid (a) of Column B, etc.

The racemic acids of Column B can be treated according to the process ofthis invention, Step (i), with 1 molar equivalent of an optically-activeamine to form a d- or l-enriched amine salt. By suitable choice ofsolvent these d- or l-enriched salts can usually be obtained ascrystalline solids, which can readily be separated from the dissolveddiastereoisomeric salts. Typical solvents include ether, ethylacetate,acetone, ethanol, isopropanol and mixtures thereof.

    Column A                                                                      ______________________________________                                        (a)                                                                                   ##STR15##                                                             (b)                                                                                   ##STR16##                                                             (c)                                                                                   ##STR17##                                                             (d)                                                                                   ##STR18##                                                             (e)                                                                                   ##STR19##                                                             (f)                                                                                   ##STR20##                                                             (g)                                                                                   ##STR21##                                                             (h)                                                                                   ##STR22##                                                             (i)                                                                                   ##STR23##                                                             ______________________________________                                    

    ______________________________________                                        Column B                                                                      (Compound I)                                                                  ______________________________________                                        (a)                                                                                   ##STR24##                                                             (b)                                                                                   ##STR25##                                                             (c)                                                                                   ##STR26##                                                             (d)                                                                                   ##STR27##                                                             (e)                                                                                   ##STR28##                                                             (f)                                                                                   ##STR29##                                                             (g)                                                                                   ##STR30##                                                             (h)                                                                                   ##STR31##                                                             (i)                                                                                   ##STR32##                                                             ______________________________________                                    

Typical optically-active amines include those listed in Column C. Otheroptically-active amines that can be used for resolution of racemic acidscan be found in standard reference works such as Wilen, "ResolvingAgents and Resolutions In Organic Chemistry", in "Topics InStereochemistry", Vol. 6, Edited by Allinger et al, John Wiley and Sons,Inc., 1971, and Wilen, "Tables of Resolving Agents and OpticalResolutions", Univ. of Notre Dame Press, London, 1972. Not all of theseoptically active amines work equally well, but generally those listed inColumn C can be induced to afford crystalline salts under solventconditions such as those described above. Once the crystallinecarboxylic acid-amine salts II are obtained, they are recrystallizedrepeatedly from a solvent such as ethyl acetate, acetonitrile, acetone,or mixtures of these solvents with ether, until their melting point andspecific rotations no longer change according to Step (ii) of theprocess of this invention. This affords salts of the optically-activeacids in one, or predominantly one, enantiomeric form. Typical salts IIare listed in Column D.

Column C Representative Resolved Amines For Step (i)

(a) l(-)brucine

(b) l(-)cinchonidine

(c) d(+)dehydroabietylamine

(d) d(+)α(1-naphthyl)ethylamine

(e) l(-)α(1-naphthyl)ethylamine

(f) d(+)ephedrine

(g) l(-)ephedrine

(h) d(+)α-methylbenzylamine

(i) l(-)α-methylbenzylamine

    __________________________________________________________________________    Column D                                                                      Representative Amine Salts II                                                 __________________________________________________________________________    (a)                                                                              ##STR33##              • brucine H.sup.⊕                         (b)                                                                              ##STR34##              • cinchonidine H.sup.⊕                    (c)                                                                              ##STR35##              • dehydroabietyl- amine H.sup.⊕           (d)                                                                              ##STR36##              • d(+)(α'-naphthyl)- ethylamine                                   H.sup.⊕                                         (e)                                                                              ##STR37##              • l(-)(α'-naphthyl)- ethylamine                                   H.sup.⊕                                         (f)                                                                              ##STR38##              • d(+)ephedrine H.sup.⊕                   (g)                                                                              ##STR39##              • l(-)ephidrine H.sup.⊕                   (h)                                                                              ##STR40##              • d(+)α-methylbenzyl- amine                                       H.sup.⊕                                         (i)                                                                              ##STR41##              • l(-)α-methylbenzyl- amine                                       H.sup.⊕                                         __________________________________________________________________________

Treatment of the salts of Column D with dilute aqueous mineral acid suchas hydrochloric acid or sulfuric acid, according to process Step (iii),affords the optically-active carboxylic acids of Column E. Some of thesalts of Column D will afford d acids, some will afford l acids. If agiven optically-active amine affords the undesired enantiomer of a givenacid, its optical antipode will, of course, afford the other enantiomerof the acid.

Esterification of the optically-active acids of Column E, according toStep (iv) of the process of this invention, employing, for instance, adiazoalkane, affords optically-active esters of this inventionexemplified in Column F.

The optically-active esters of Column F can then be reduced tooptically-active aldehydes of Column G by the action of NaAl(OCH₂ CH₂OCH₃)₂ H₂. These optically-active aldehydes are useful precursors to theoptically active 8-azaprostanoids.

    ______________________________________                                        Column E                                                                      (Acids III, d or l)                                                           ______________________________________                                        (a)                                                                                   ##STR42##                                                             (b)                                                                                   ##STR43##                                                             (c)                                                                                   ##STR44##                                                             (d)                                                                                   ##STR45##                                                             (e)                                                                                   ##STR46##                                                             (f)                                                                                   ##STR47##                                                             (g)                                                                                   ##STR48##                                                             (h)                                                                                   ##STR49##                                                             (i)                                                                                   ##STR50##                                                             ______________________________________                                    

    ______________________________________                                        Column F                                                                      (Esters IV, d or l)                                                           ______________________________________                                        (a)                                                                                   ##STR51##                                                             (b)                                                                                   ##STR52##                                                             (c)                                                                                   ##STR53##                                                             (d)                                                                                   ##STR54##                                                             (e)                                                                                   ##STR55##                                                             (f)                                                                                   ##STR56##                                                             (g)                                                                                   ##STR57##                                                             (h)                                                                                   ##STR58##                                                             (i)                                                                                   ##STR59##                                                             ______________________________________                                    

    ______________________________________                                        Column G                                                                      Aldehyde Precursors For 8-Azaprostanoids                                      ______________________________________                                        (a)                                                                                   ##STR60##                                                             (b)                                                                                   ##STR61##                                                             (c)                                                                                   ##STR62##                                                             (d)                                                                                   ##STR63##                                                             (e)                                                                                   ##STR64##                                                             (f)                                                                                   ##STR65##                                                             (g)                                                                                   ##STR66##                                                             (h)                                                                                   ##STR67##                                                             (i)                                                                                   ##STR68##                                                             ______________________________________                                    

UTILITY

The optically-active intermediates of this invention are useful asprecursors to optically-active 8-azaprostanoids which in turn have valueas drugs and diagnostic agents. For example, the 8-azaprostanoids can beused to prepare gastric cytoprotective agents which, because theyprotect the mucosa of the stomach and small intestine, are of potentialvalue in hastening the healing of peptic ulcers, or for treatinginflammatory bowel diseases, such as colitis, or preventing ulcerativechanges in the gastro-intestinal tract caused by non-steroidalantiinflammatory agents.

The advantages of having available different optical forms of the8-azaprostanoids lies in differences in the kind of biological activityexhibited by these different forms. For example, some of the opticalforms (or optical isomers) of the 8-azaprostanoid esters and acidsderived from the optically-active intermediates of this invention arepotent as cytoprotective agents in experimental animals, being severaltimes more potent on a mg/kg basis than the racemic oroptically-inactive forms of these 8-azaprostanoid esters and acids.

Some of the optically-active esters and acids, especially the acids, arepotent inhibitors of histamine-induced bronchoconstriction, as a measureof potential anti-asthma activity. However, some of the optical isomerswhich have relatively low potencies in cytoprotection or bronchodilationtests exhibit prostaglandin-antagonism activity. That is, these opticalisomers can inhibit some of the biological effects ordinarily broughtabout by natural prostaglandins, e.g., prostaglandin E₁, and by virtueof this property they are potentially useful as reagents for biochemicalresearch or as medical diagnostic agents or as anti-diarrheal agents.

One important aspect of the process of this invention that distinguishesit from other processes that have been used to prepare8-azaprostaglandins having natural (R) configurations at C-12, is thatit affords both natural (R) and unnatural (S) forms from readilyavailable starting materials. As mentioned above, some of the C-12unnatural isomers are relatively weak as prostaglandin mimics but theyare more effective as prostaglandin antagonists. Table 1 summarizesvarious cytoprotection data.

The data of Table 1 are from tests similar to one described by Robert[U.S. Pat. No. 4,097,603 (1978)] in which fasted, male rats were treatedwith 8-azaprostanoids orally. Then, at various times later they weretreated orally with 1.0 ml of absolute ethanol. The rats were sacrificedafter ethanol administration and the stomachs were removed, inspected,and rated. The ED₅₀ values of Table 1 represent the doses of8-azaprostanoids that gave 50% protection from the necrosis andinflammation of the stomach caused by ethanol. For comparison, valuesare given for the natural prostaglandin, PGE₁, and for racemic7-[2-oxo-5(4,4-difluoro-3-hydroxy-1n-dec-1(E)-enyl)-1-pyrrolidinyl]heptanoicacid, which is identified in Table 1 as compound 8. The correspondingracemic tert-butyl ester is identified as 7. The structures of 7 and 8,each of which is a mixture of 4 optical isomers, are as follows:##STR69##

                  TABLE 1                                                         ______________________________________                                                           Percent                                                                       Protection,                                                                              ED.sub.50                                                Example   2 mg/kg    mg/kg at Peak                                   Compound No.       1 hr*      Peak Time**                                                                            Time**                                 ______________________________________                                        PGE.sub.1          --         .011     5 min                                  7                  32                                                         7l(15R,S)                                                                              1C        59                                                         7d(15R,S)                                                                              1C        -5                                                         7l(15R)  1D        59                                                         7l(15S)  1D         9                                                         8        --        91          .0035   15                                     8l(15R)  1E        --          .0007   15                                     8l(15S)  1E        --         .010     15                                     ______________________________________                                         *"1 hr" refers to the 1 hour interval between administration of compound      and subsequent administration of ethanol.                                     **"Peak Time" refers to the interval between administration of compound       and administration of ethanol at which greatest protection is observed.  

Some differences in biological activities of the racemic forms anddifferent optical isomers of these 8-azaprostanoids can be seen in thedata presented in Table 1. For example, optical isomer 8l(15R) is morepotent as a cytoprotective agent than its racemic form 8. On the otherhand, optically active ester 7d(15R,S) is less potent than its racemicform 7. In other tests, optically active ester 7d(15R,S) was more potentthan 7 as an antagonist of PGE₁ in in vitro tests on rat stomach strips.

EXAMPLES

The following Examples illustrate the invention. Temperatures are indegrees Celsius.

EXAMPLE 1 rac tert-Butyl 7-[2-Oxo-5-carboxy-1-pyrrolidinyl]heptanoate(2). ##STR70##

The compound, rac-tert-butyl7-(2-oxo-5-methoxycarbonyl-1-pyrrolidinyl)heptanoate, (1) (32.7 g, 0.1mole) which had been purified by distillation through a wiped-filmmolecular still, was dissolved in 60 ml of methanol and, with stirringand cooling so that the reaction mixture stayed at 15°±3°, 1.0 N NaOHwas added dropwise. When 90 ml of the caustic had been added, 3 drops ofa 1% phenolphthalein indicator solution was added and enough additionalcaustic was added until a slight pink color persisted for 10 min. Atotal of 93.5 ml of 1 N NaOH was thus used. The mixture was concentratedunder vacuum, mixed with 200 ml of water, and the water solution washedtwice with ether, which was discarded. The aqueous solution was cooledin an ice bath and treated with 110 ml of 1.0 N HCl dropwise. Extractionwith ether, drying over MgSO₄, and evaporation of the ether, gave 28 g(89%) of white crystalline racemic acid 2, m.p., 49° to 51°. For asample prepared similarly: Anal. Calcd. for C₁₆ H₂₇ NO₅ : C, 61.32; H,8.68; N, 4.47; Found: C, 60.86; H, 8.52; N, 4.80.

Similarly, 65.6 g of crude racemic diester 1 that had not beenpreviously purified by distillation was saponified in 80 ml of methanolby slow addition of 1.0 N NaOH at 35° over 2 hrs. The racemic acid 2 wasisolated similarly and amounted to 51 g, m.p. 48° to 50°. Thisrepresents a significant simplification of the process used forpreparing acid 2 because it eliminates the need for moleculardistillation of the crude diester 1 obtained as described in U.S. Pat.No. 3,975,399.

Steps (i) and (ii) Of Process Salts of optically-active acids 2l and 2dwith optically-active amines l(-)2-methylbenzylamine andd(+)2=methylbenzylamine (3l and 3d) ##STR71##

A solution of 66.37 g (0.212 mole) of racemic acid 2 in 212 ml of etherwas stirred with ice cooling under nitrogen while 25.66 g (0.212 mole)of d(+)-α-methylbenzylamine diluted to 50 ml with ether was addedquickly from a dropping funnel. The mixture was seeded with crystals ofd(+) amine salt (obtained earlier) and stirred at room temperature forabout 23 hrs. The crystalline solid was collected under nitrogen (thewet salt is hygroscopic, the pure salt is not), affording 24.9 g of salt3d. This salt was recrystallized from 50 ml of ethyl acetate, affording20.3 g of pure salt 3d, m.p. 100° to 102°.

The ethyl acetate and ether filtrates from above were combined, cooledin ice, and treated with 125 ml of 2 N HCl with stirring. The organiclayer was separated, washed with two 75-ml portions of 1 N HCl, washedtwice with saturated NaCl, and dried over Drierite. Evaporation of thesolvent gave 51.96 g of acid 2 as an oil enriched in one enantiomer.This oil was dissolved in 200 ml of ether, and treated with 20.1 g ofl(-)α-methylbenzylamine in 50 ml of ether at 0°. The mixture was seeded,kept at 0° for 1 hr, and filtered, giving 20.7 g of the salt 3l, whichwas recrystallized from 40 ml of ethyl acetate to give 15.4 g of salt3l, m.p. 100° to 103°.

The combined ether and ethyl acetate filtrates from precipitation of thesalt 3l were treated with HCl as in the previous paragraph and the crudeacid 2 obtained was treated with one equivalent ofd(+)α-methylbenzylamine, etc., as above, to give in a total of threecycles 30.4 g of recrystallized salt 3d. Two cycles gave a total of 25.4g of recrystallized salt 3l.

Very pure samples of both salts, prepared similarly but recrystallizedseveral times from ethyl acetate, had m.p.'s of 101° to 103° (mixedm.p.'s 73° to 90°). For salt 3d: Anal. Calcd. for C₂₄ H₃₈ N₂ O₅ : C,66.23; H, 8.81; N, 6.45; Found: C, 66.40; H, 8.74; N, 6.40.

Specific rotation of the optically-active salts 3d and 3l did not changesignificantly after two crystallizations from ethyl acetate (c=3.33,ethanol):

    ______________________________________                                                   3d          3l                                                     ______________________________________                                        [α].sub.D                                                                             -2.8°  +2.3°                                      [α].sub.365                                                                          -50.6° +49.0°                                      ______________________________________                                    

Step (iii) of Process d(+) tert-Butyl7-[2-Oxo-5-carboxy-1-pyrrolidinyl]heptanoate (2d) and l(-) tert-Butyl7-[2-Oxo-5-carboxy-1-pyrrolidinyl]heptanoate (2l) ##STR72##

Treatment of 0.434 g of salt 3d with 50 ml of ether, 8 ml of water, and2.0 ml of 1 N HCl gave in the ether layer after washing with 10 ml of0.1 N HCl, and then washing with saturated NaCl and drying over MgSO₄,0.303 g (97%) of the resolved acid 2d as a colorless liquid, [α]_(D)+0.9° (EtOH). Similarly, salt 3l was converted to resolved acid 2l[α]_(D) -1.0° (EtOH).

Acid 2d is one, or predominantly one, enantiomer, believed to have theabsolute configuration represented by 2(R), whereas acid 2l is one, orpredominantly one, enantiomer believed to have the absoluteconfiguration represented by 2(S). ##STR73##

It is to be understood that the absolute configurations representedabove by structures 2(R) and 2(S) and subsequently for compounds derivedfrom these acids are based on signs of optical rotation, chromatographicbehavior, and biological properties of interrelated members of theseries of compounds.

Step (iv) Of Process d(+) tert-Butyl7-[2-Oxo-5-methoxycarbonyl-1-pyrrolidinyl]heptanoate (1d) and l(-)tert-Butyl 7-[2-Oxo-5-methoxycarbonyl-1-pyrrolidinyl]heptanoate (1l)##STR74##

Treatment of resolved acid 2d (9.06 g), prepared similarly to thatdescribed above, with excess diazomethane in ether, gave 8.53 g of thecorresponding resolved methyl ester (1d); [α]_(D) +6.2° (±0.1°), [α]₃₆₅-31.4° (±0.1°), (c=6.67 EtOH).

Treatment of resolved acid 2l (9.4 g) prepared in a manner similar tothat described for 2d gave 8.68 g of ester 1l (EtOH); [α]_(D) -6.3°(±0.1°), [α]₃₆₅ +31.5° (±0.1°) (c=6.67 EtOH).

Ester 1d is one or predominantly one enantiomer believed to be 1(R),whereas 1l is one or predominantly one enantiomer believed to be 1(S):##STR75##

Preparation of Aldehydes l and d tert-Butyl7-(2-Oxo-5-formyl-1-pyrrolidinyl)heptanoate 4l and 4d ##STR76##

A solution of 3.27 g of resolved ester 1d in 15 ml of tetrahydrofuran(THF) was cooled to -78° and 2.5 ml of a 70% solution of sodiumbis(2-methoxyethoxy)aluminum hydride in toluene (Vitride T®) in 10 ml ofTHF was added dropwise with stirring. The mixture was stirred for 2.5hrs with continued cooling, poured into about 300 ml of saturated oxalicacid solution, and extracted three times with ether. The ether was driedover CaSO₄ and evaporated, giving 2.49 g (84%) of resolved aldehyde 4las a colorless oil. The aldehyde was dried further, dehydrating thealdehydrol present, by dissolving it in toluene and removing the tolueneunder reduced pressure at about 50°.

Similarly, 4.9 g of resolved ester 1l in 20 ml of THF at -78° wastreated with 3.8 ml of Vitride T® solution in 15 ml of THF for 6 hrs,giving 3.91 g (71%) of resolved aldehyde 4d as a colorless oil; pmr(CDCl₃, TMS) 9.58 ppm (d, J=2.5 Hz CHO, 1) ppm, and other peaksidentical to those observed for the racemic (d,l) tert-butyl7-(2-oxo-5-formyl)heptanoate.

In a modified procedure, 7.1 g (22.6 mmoles) of ester 1l in 35 ml of THFat -78° was treated dropwise with a solution of 5.2 ml of Vitride T® in50 ml of THF. The addition was carried out very slowly over 1.25 hrs andthen the reaction mixture was kept at -78° for 5 hrs before pouring into400 ml of water containing 15 g of oxalic acid and saturated withrespect to NaCl. After 3 extractions with ether, drying the ether overMgSO₄ and CaSO₄, and evaporation of the ether, there was obtained theoptically-active aldehyde 4d. Aldehyde 4d was then dried by evaporationof its toluene solution as described above, giving 6.9 g of aldehyde 4das a light yellow oil, [α]₃₆₅ +29.4° (c=3.33 ethanol).

Similarly, ester 1d was treated with Vitride T® by this modifiedprocedure giving aldehyde 4l as a light yellow oil, [α]₃₆₅ -24.8 (c=3.33ethanol).

Optically-active aldehyde 4l is believed to be predominantly 4(R) andoptically-active aldehyde 4d is believed to be predominantly 4(S):##STR77## Several 8-azaprostanoids were prepared from these aldehydesaccording to the procedures of Examples 1A to 1F.

EXAMPLE 1A Preparation of 8-Azaprostanoids l and d tert-Butyl7-[2-Oxo-5-(R orS)-5-(4,4-dimethyl-3-oxo-1n-oct-1(E)-ene)-1-pyrrolidinyl]heptanoate (5lor 5d) ##STR78##

To 0.325 g (8.04 mmoles) of 59.6% sodium hydride in oil that had beenwashed three times with petroleum ether under nitrogen was added 50 mlof dry ethylene glycol dimethyl ether ("glyme") and then to this stirredsuspension was added dropwise a solution of 2.30 g (9.2 mmoles) ofdimethyl 3,3-dimethyl-2-oxoheptylphosphonate in 25 ml of glyme. Themixture was stirred for 30 min after the addition was completed, thesolution of the sodium salt of the phosphonate was cooled to -40°, andthen a solution of 2.49 g (8.38 mmoles) of the aldehyde 4l in 10 ml ofglyme was added. The reaction mixture was kept at -40° for 10 minutesand then allowed to warm slowly to 0°, at which temperature it was keptfor 40 min. A solution of 1 ml of water saturated with NH₄ Cl was addedand then the organic solvent was removed under reduced pressure. Theresidue was mixed with 100 ml of water and extracted three times withether. The ether was washed with water, dried, and evaporated, giving3.8 g of the optically-active 8-azaprostanoid ketone 5l. Purification byHPLC (2:1 ethyl acetate/hexane) gave 2.4 g of 5l (71%) in a colorlessoil; HRMS:

    ______________________________________                                        meas.     calcd.      assignment                                              ______________________________________                                        421.3184  421.3190    C.sub.25 H.sub.43 O.sub.4 N                             365.2577  365.2564    M--C.sub.4 H.sub.8                                      348.2543  348.2536    M--C.sub.4 H.sub.9 O                                    308.1863  308.1860    M--(C.sub.4 H.sub.8 + C.sub.4 H.sub.9)                  ______________________________________                                    

The pmr spectrum of 5l (220 MHz, CDCl₃, TMS) agreed well with theassigned structure, showing an AB doublet centered at about 6.5 ppm, onepair of peaks being split further into doublets. For 5l [α]_(D) -3.2°,[α]₄₀₅ =-14.6° (c=3.33, dioxane).

Similarly, aldehyde 4d was converted to 8-azaprostanoid ketone 5d; HRMSand pmr analyses gave essentially identical results. For 5d [α]_(D)=+3.4°, [α]₄₀₅ =+15.1° (c=3.33, dioxane).

Optically-active 8-azaprostanoid ketones 5l and 5d were eachpredominantly one enantiomer believed to have the absoluteconfigurations represented, respectively, by structures 5(R) and 5(S).##STR79##

EXAMPLE 1B l and d tert-Butyl 7-[2-Oxo-5(R orS)-5-(4,4-difluoro-3-oxo-1n-dec-1(E)-ene)-1-pyrrolidinyl]heptanoate 6land 6d ##STR80##

A suspension of 12.4 mmoles of NaH in glyme was prepared by washingunder nitrogen 0.540 g of 55% NaH/oil with petroleum ether and thenadding 20 ml of glyme. With cooling in an ice bath and with stirring, asolution of 4.25 g (14.8 mmoles) of dimethyl3,3-difluoro-2-oxo-n-nonylphosphonate in 15 ml of glyme was addeddropwise over about 15 min. The sodium salt was stirred at 0° for 5 minand then to the clear solution was added 4.1 g (13.8 mmoles) of aldehyde4l in 15 ml of glyme. The reaction mixture was heated at refluxtemperature for 1.5 hrs, cooled, and concentrated under reduced pressureat 40°. The residue was mixed with saturated NH₄ Cl solution andextracted with ether. The ether was dried (MgSO₄ /CaSO₄) and evaporated,and the crude ketone 6l was purified by HPLC (EtOAc then 3:1EtOAc/hexane). The pure, optically-active 8-azaprostanoid 6l thusobtained was a colorless oil weighing 2.77 g (49% yield); [α]_(D) -0.5°;[α]₄₀₅ -20.7° (c=3.33, dioxane); HMRS calcd for C₂₁ H₃₃ O₄ NF₂ (m/e ofM-C₄ H₉) 401.2376; meas. 401.2401.

A suspension of 19.6 mmoles of NaH in 60 ml of glyme was preparedsimilarly from 0.867 g of 55% NaH/oil. This was kept at -5° to -8° whilea solution of 5.89 g (20.6 mmoles) of dimethyl3,3-difluoro-2-oxo-n-nonyl-phosphonate in 45 ml of glyme was addeddropwise over 1 hour; then 6.7 g (22.6 mmoles) of aldehyde 4d in 30 mlof glyme was added all at once and the mixture was stirred at roomtemperature for 2 hrs. The mixture was concentrated under vacuum, mixedwith 130 ml of water containing 15 g of NH₄ Cl, and extracted withether. The ether was dried and evaporated and the crude product waspurified by HPLC (1:1 EtOAc/hexane), affording pure, optically-active8-azaprostanoid ketone 6d (TLC, R_(f) =0.5, 1:1 EtOAc/hexane), [α]_(D)+1.1°, [α]₄₀₅ +20.8° (c= 3.33, dioxane). The pmr spectrum confirmed thestructure.

¹⁹ F nmr spectra of samples of these two 8-azaprostanoid ketonesprepared similarly showed (CDCl₃, F-11) proton-decoupled singlets at-107.46 ppm.

Optically active 8-azaprostanoid ketones 6l and 6d are eachpredominantly a single enantiomer. Their absolute configurations arebelieved to be as represented by structures 6(R) for 6l and 6(S) for 6d.##STR81##

EXAMPLE 1C Optically-active (l) tert-butyl 7-[2-oxo-5(R orS)-5-(4,4-difluoro-3(R,S)hydroxy-1n-dec-1(E)-enyl)-1-pyrrolidinyl]heptanoate[7l(15R,S)]and optically-active (d) tert-butyl 7-[2-oxo-5-(S orR)-5-(4,4-difluoro-3(R,S)hydroxy-1n-dec-1(E)-enyl)-1-pyrrolidinyl]heptanoate[7d(15R,S)]##STR82##

A mixture of 2.6 g of optically-active 8-azaprostanoid ketone 6l and 0.5g of NaBH₄ in 50 ml of ethanol was kept at -20° for 3.3 hrs and thenpoured into 500 ml of saturated NH₄ Cl solution and extracted with ethylacetate. The ethyl acetate extract was dried (MgSO₄ /CaSO₄) andevaporated giving the optically-active mixture of 8-azaprostanoids7l(15R,S). Analysis by TLC (silica gel, EtOAc) showed this to be anapproximately 50:50 mixture of the two C-15 epimeric alcohol (R_(f)=˜0.5); analytical HPLC (5% ethanol in cyclopentane) showed a ratio ofabout 53/47 (less mobile isomer to more mobile isomer). HRMS showed avery weak 459 parent ion (M) and a stronger M-C₄ H₉ ion C₂₁ H₃₄ O₄ NF₂,calcd 402.2454, meas. 402.2483; ¹⁹ F nmr (CDCl₃, TMS, F-11) shows twosets (2 diastereomeric) of AB patterns (proton decoupled) with each setof peaks centered at -107.18 (weak), -109.82 (strong), -111.26 (strong),-113.92 (weak) ppm. Specific rotations for another sample preparedsimilarly [α]_(D) -11.6°, [α]₃₆₅ -57.9° (c=3.33, EtOH).

In like manner, reduction of 0.8 g of ketone 6d by 0.15 g of NaBH₄ in 25ml of ethanol at -20° for 5 hrs gave the optically-active mixture of8-azaprostanoids 7d(15R,S); HRMS identical to that of 7l(15R,S); [α]_(D)+11.8°, [α]₃₆₅ +58.4° (c=3.33, EtOH).

EXAMPLE 1D Four optically-active isomers of tert-butyl 7-[2-oxo-5(R orS)-5-(4,4-difluoro-3(R or S)-3-hydroxy-1n-dec-1(E)-enyl)-1-pyrrolidinyl]heptanoate; 7l(15R), 7l(15S), 7d(15R) and 7d(15S)

Alcohols 7l(15R,S) being diastereomeric can be separated bychromatography. Likewise, alcohols 7d(15R,S) can be separated bychromatography. A particularly effective solvent system for theseseparations when they are carried out by HPLC on silica gel is 5%isopropyl alcohol in cyclopentane. In this manner, alcohol 7l(15R,S) canbe separated into optically-active alcohols 7l(15R) and 7l(15S) andalcohol 7d(15R,S) can be separated into optically active alcohols7d(15S) and 7d(15R). These four optically-active alcohols arepredominantly single optical isomers with what are believed to be thefollowing absolute configurations. ##STR83##

Alcohol 7l(15R) (the slower-moving diastereomer) had [α]_(D) +1.9°,[α]₃₆₅ -11.0° (c=3.33, ethanol); alcohol 7l(15S) (the faster-movingdiastereomer) had [α]_(D) -29.7°, [α]₃₆₅ -122.4° (c=3.33, ethanol).Alcohol 7d(15S) (slower moving) had [α]_(D) -1.3°, [α]₃₆₅ +13.5°(c=3.33, ethanol) and alcohol 7d(15R) (faster moving) had [α]_(D)+28.0°, [α]₃₆₅ +114.8° (c=3.33, ethanol). The HRMS spectra of these fouralcohols were essentially identical, and supported the molecular ionassignment C₂₅ H₄₃ O₄ NF₂. The ¹⁹ F nmr (CDCl₃, TMS, F-11) spectraconfirmed both the structure of these alcohols and the fact that thediastereomeric components had been separated since each show a single ABpattern (when proton decoupled); e.g., for 7l(15 R) single peaks werefound at -107.23 (weak), -109.86 (strong), -111.37 (strong) and -114.01(weak) ppm and for 7l(15S) single peaks were found at -107.49 (weak),-110.14 (strong), -111.38 (strong), and -114.04 (weak) ppm.

EXAMPLE 1E Four optically-active isomers of 7-[2-oxo-5(R orS)-5-(4,4-difluoro-3(R orS)-3-hydroxy-1n-dec-1(E)-enyl)-1-pyrrolidinyl)heptanoic acid [8l(15R),8l(15S), 8d(15S), and 8d(15R)]

A solution of 0.390 g of the tert-butyl ester 7l(15R) in 2 ml oftetrahydrofuran was added with stirring to 10 ml of 85% phosphoric acidcooled in an ice bath. The ice bath was then removed and the mixturestirred at ambient temperature for about 4 hours. It was then pouredinto 50 cc of saturated NaCl solution and extracted three times withethyl acetate, which was dried and evaporated. Purification of the acidthus obtained by dissolving it in 5% NaHCO₃ and then regenerating it byacidification, gave 0.280 g of optically active 8-azaprostanoid acid8l(15R). This acid is one, or essentially one, optical isomer. Treatmentof the other optically-active esters 7l(15S), 7d(15R), and 7d(15S)similarly with phosphoric acid gave the corresponding acids 8l(15S),8d(15R), and 8l(15S), each being one, or essentially one, opticalisomer. The absolute configurations of these optically-active acids arebelieved to be as indicated in the following structures. ##STR84##

EXAMPLE 1F Optically-active (l) 7-[2-Oxo-5(R orS)-5-(4,4-difluoro-3(R,S)hydroxy-1n-dec-1(E)-enyl)-1-pyrrolidinyl]heptanoic[8l(15R,S)] and optically-active (d) 7-[2-Oxo-5(S orR)-5-(4,4-difluoro-3-(R,S)hydroxy-1n-dec-1-(E)-enyl)-1-pyrrolidinyl]heptanoic[8d(15R,S)]. ##STR85##

Instead of separating the diastereomers of optically-active8-azaprostanoid esters 7l(15R,S) and 7d(15R,S) as described in Example1D, these esters can be hydrolyzed directly to correspondingoptically-active acids that are epimeric at C-15. Thus, treatment ofthese esters in tetrahydrofuran with 85% phosphoric acid in a manneranalogous to the procedure described in Example 1E gave optically-active8-azaprostanoid acids 8l(15R,S) and 8d(15R,S).

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A compound of theformula ##STR86## wherein the asterisk means that one enantiomer ispredominant and wherein R is a protonated optically-active amine moietyselected from the group consisting of l(-)brucine, l(-) cinchonidine,d(+)dehydroabietylamine, d(+)α(1-naphthyl)ethylamine,l(-)α(1-naphthyl)ethylamine, d(+)epherdrine, l(-)ephedrine,d(+)α-methylbenzylamine, l(-)α-methylbenzylamine.
 2. A compoundaccording to claim 1, ##STR87## where R is the protonatedα-methylbenzylamine moiety derived from optically-active d or lα-methylbenzylamine.
 3. A compound according to claim 1, ##STR88## whereR is the protonated ephedrine moiety derived from optically-active d orl ephedrine.